Characterizing the neuronal circuits mediating drug reinforcement is necessary for understanding the neurobiological basis of the addictive disorders. This research project proposes experiments to identify and characterize neurohumors and brain loci that initiate and mediate cocaine reinforcement processes. This will be accomplished by allowing rats to intracranially self-administer cocaine directly into discrete brain regions. Intermittent schedules of reinforcement and two-lever discrimination procedures will be used to differentiate the reinforcing properties of self-administered cocaine from elicited behaviors. Attenuation of self-administration by neurotransmitter receptor antagonists will be studied to demonstrate the specificity of the receptors responsible for these effects. Horseradish peroxidase and (3H)-proline-(3H)-leucine transport will identify cell bodies of neurons projecting to or projection areas of neurons at the self-administration site. The potential involvement of more distal neurons in these processes will be assessed by concurrently measuring turnover rates of acetylcholine, dopamine, norepinephrine, serotonin, aspartate, gamma-aminobutyric acid and glycine in small brain regions of rats intracranially self-administering cocaine and in yoked-vehicle infused littermates. The role of these neuronal pathways that potentially mediate the reinforcing properties of cocaine will be characterized with neurotoxin lesions or intracranial infusion of receptor antagonists into these areas and assessing effects on the intracranial self-administration. The specificity of the involvement of identified pathways projection areas or receptors in cocaine reinforcement will be determined using neurotoxin lesions or intracranial injections of specific neurotransmitter receptor antagonists directly into brain regions of animals concurrently responding on food, water and intravenous cocaine reinforcement schedules. Knowledge of the neuronal pathways initiating and mediating cocaine reinforcement would significantly advance understanding of brain-behavior interactions and possibly suggest new approaches to the treatment of the addictive disorders.